The known compound of formula (I), (3R,4R)-3-hydroxy-4-hydroxymethylpyrrolidine, is a key intermediate compound for the synthesis of certain of the applicant's inhibitor compounds, including potent PNP inhibitors (see for example PCT/NZ03/000186). The enantiomer of the compound for formula (I) is the compound of formula (Ia) and this is also useful as an intermediate for the synthesis of PNP inhibitors.

Makino and Ichikawa (K. Makino and Y. Ichikawa, Tetrahedron Letters (1998) 39, 8245) have reported a synthesis of compound (I). The requisite chirality of compound (I) is introduced using a Sharpless asymmetric epoxidation.
Karlsson and Högberg (S. Karisson and H.-E. Högberg, Tetrahedron: Asymmetry (2001) 12, 1977) describe an alternative synthesis method. In this method, chirality is introduced using a chiral sultam auxiliary.
Galeazzi et al. (R. Galeazzi, G. Martelli, G. Mobbili, M. Orena and S. Rinaldi, Tetrahedron: Asymmetry (2004) 15, 3249) prepared compound (I) by the addition of (S)-1-phenylethylamine to an ethyl 2-silyloxy-3-methoxycarbonyl-but-3-enoate.
Filichev et al. (V. V. Filichev and E. B. Pedersen, Tetrahedron (2001) 57, 9163; V. V. Filichev, M. Brandt and E. B. Pedersen, Carbohydrate Research (2001) 333, 115) have used chiral starting materials to produce compound (I): For example, compound (I) can be prepared from diacetone-D-glucose or from D-xylose. However, both synthetic procedures are complex and require many reaction steps.
An alternative method for introducing chirality involves the use of biological catalysts. For example, Hansen and Bols (S. U. Hansen and M. Bols, Acta Chemica Scandinavica(1998) 52, 1214) attempted the enzymatic resolution of the N-Boc derivative of racemic trans-4-hydroxymethylpyrrolidin-3-ol using immobilised lipases from Candida antarctica and Mucor mihei. This method focuses on attempting to resolve the diol by enzymatic means. However, poor enantiomeric excesses were obtained in this way, resulting in only small amounts of compound (I) being made available for use as an intermediate in the preparation of other compounds. Low product yields mean considerable wastage and therefore high overall cost.
The published syntheses of compound (I) are deemed unsatisfactory as commercially viable routes to this valuable intermediate compound. There has been an ongoing need to overcome this problem by developing an improved method which employs only a few reaction steps and with an acceptable overall product yield.
It is known that lipase catalysed resolution of carbocyclic cis- and trans-β-hydroxy esters by O-acylation can provide enantiopure compounds in high yields (L. M. Levy, J. R. Dehli and V. Gotor, Tetrahedron: Asymmetry (2003) 14, 2053). However, it is very difficult to predict the reactivity of an enzyme to a potential substrate. The specificity of enzymes is well known in the art. Even when a particular compound is found to be an enzyme substrate there is often little certainty as to reaction yield and enantiomeric purity of the product.
The applicant has shown that compound (I) can be prepared in high yield and high enantiomeric excess from a (±)-trans-1-N-protected-4-hydroxypyrrolidine-3-carboxylic acid alkyl ester, via lipase catalysed esterification (WO 2005/033076). However, that preparation method suffers from several key disadvantages. In particular, the method requires chromatographic purification steps. Such steps are expensive processing steps. They add considerable cost to the overall method and they typically result in a lower yield of the compound. These disadvantages are especially apparent when the method is carried out on large scale. There has therefore been a need for an improved process for preparing the compounds of formulae (I) and (Ia) that avoids these disadvantages, particularly for the scale of process required for commercial production.
The applicant has now developed an improved method for preparing 3-hydroxy-4-hydroxymethylpyrrolidine compounds, using readily available starting materials. This new route overcomes the problems often encountered with syntheses that employ achiral starting materials. It involves fewer chemical transformations than published methods, and allows for the preparation of the desired compounds in high yield and enantiomeric excess. Most importantly, the improved method avoids the need for any chromatographic purification steps. This surprising discovery provides an advantage over known processes, including the process described in WO 2005/033076, that enables a significantly simpler and cost effective route to 3-hydroxy-4-hydroxymethylpyrrolidine compounds, and other compounds, such as PNP inhibitors, that may be prepared from them.
It is therefore an object of the invention to provide an improved method for preparing 3-hydroxy-4-hydroxymethylpyrrolidine compounds.